A substantial number of studies strongly indicate that the viral envelope gene (env) determines cell-specificity of HIV-1 and suggest that the cell- specificity of HIV-1 is one of the keys to understanding the complex nature of disease processes in AIDS. HIV-1, with high replicative ability for macrophages, may play important roles in the transmission and persistence of HIV-1, whereas biotypes trophic for T-lymphocytes may be responsible for the clinical manifestation of immunodeficiency. The molecular mechanisms by which cell-type-specific HIV-1 influence the disease course and manifestations, however, remain to be elucidated. The proposed studies will explore the significance of viral cell- specificity as a determinant for the nature of the disease process in AIDS using the SIV/rhesus macaque model system. We have isolated SIVmacl55/TT variant from the lymph nodes of a rhesus macaque that died following infection with cloned SIVmac239. The SlVmacl55/TT variant strongly showed T cell-adapted properties in culture; e.g., higher replicative and cytopathic ability for T-lymphocytes than the parental SIVmac239, but replicated poorly in macrophages. We have also isolated SlVmacl55/MT variant with high replicative ability for macrophages from the lymph nodes of the same animal. In contrast to most macrophage-competent HIV-1 and SlV, the MT variant replicated poorly in rhesus T lymphocytes. Sequence analysis revealed variant specific amino acid changes in the V1 to V2 and V3 regions of gpl20. Ev/T3 env recombinant containing the TT-derived gp120 sequences and Ev/M3 env recombinant containing the MT-derived gp120 sequences displayed strong replicative ability for T-lymphocytes and macrophages, respectively. Sequence analysis revealed that TT type env variant was specifically present in the lymph nodes, but MT type env variants were present in the lymph nodes and brain of the animal. These data suggest that the gpl20 of SlV not only is important for determining the cell-specificity, but may also contribute to the tissue localization of SIV in vivo. In the proposed studies, we will investigate the significance of viral cell-specificity in determining the disease processes of AIDS using the strongly T cell-adapted Ev/T3 and macrophage adapted Ev/M3 cloned SIVs. We will biologically and genetically investigate the pathophysiological events that occur immediately after virus infection (at acute viremic phase) and from clinical latency to a late stage by Ev/T3 and Ev/M3 infection. We will compare the differences of host responses to each cell- type-specific SlV. The significance of viral cell-specificity for replicative ability in vivo, tissue-distribution and pathogenicity will be investigated. Genetic changes in the gp120 of each SIV during the course of infection will be identified. Investigation of the interactions between infected host and cell-type-specific SlV in vivo may have important implications in the design of vaccine and therapeutic strategies for the HIV-1 infected individuals.